BJA Education, 20(7): 220e225 (2020)
doi: 10.1016/j.bjae.2020.02.006
Matrix codes: 1A02,
2D06, 3D00
Anxiolytic premedication for children
S. Heikal and G. Stuart*
Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
*Corresponding author: grant.stuart@gosh.nhs.uk
Learning objectives
By reading this article, you should be able to:
 Describe the role of sedative premedication in
managing preoperative anxiety in children.
 Discuss the considerations for selecting which
premedication to use.
 Explain that midazolam may cause a paradoxical
reaction in some patients.
A child’s preoperative anxiety can pose a significant challenge
for the anaesthetic team and can be distressing for parents.
Evidence suggests that preoperative anxiety is associated with
adverse outcomes, both clinical (increased requirements for
analgesics and emergence delirium) and behavioural (sleep
disturbances and enuresis).1,2 Many techniques can be used to
reduce anxiety (Table 1). Non-pharmacological techniques
must be considered for all anxious children and may be used
in conjunction with premedication, or independently. The
evidence base for these is growing, but a detailed discussion is
beyond the scope of this article.3 Sedative premedication is
used when alternative techniques have failed, for those
needing multiple operative procedures, for those who have
previously had a traumatic perioperative experience and for
those with special needs (e.g. autistic spectrum disorder) that
Sarah Heikal MCEM FRCA is a specialty registrar in anaesthesia in
the Severn Deanery. She has also completed a year of advanced
training in paediatric anaesthesia at Great Ormond Street Hospital
for Children.
Grant Stuart FRCA is a consultant paediatric anaesthetist at Great
Ormond Street Hospital. His major interests include anaesthesia for
rare diseases, particularly metabolic illness; TIVA; spinal surgery;
and sedation, particularly the clinical use and applications for dex-
medetomidine in children.
Accepted: 28 February 2020
Crown Copyright © 2020 Published by Elsevier Ltd on behalf of British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: permissions@elsevier.com
Advance Access Publication Date: 21 April 2020
Key points
 Preoperative anxiety in children is associated
with adverse clinical and behavioural outcomes.
 Multiple techniques may be valuable in managing
preoperative anxiety.
 The need for sedative premedication should be
considered during the preoperative assessment
of every child.
 Many factors may influence the choice premed-
ication, including the pharmacological profile,
possible adverse effects and the presence of any
comorbid conditions.
 More work is required to clarify weight-based
dosing in obese patients.
limit the child’s ability to cooperate. It may also be used in
conjunction with non-pharmacological techniques.
Identifying children who are likely to experience preoper-
ative anxiety is an essential step in optimising their care. A
number of tools, such as the modified Yale Preoperative
Anxiety Scale, can provide an observational measure of anx-
iety, but these are used for research rather than for clinical
purposes.4 Factors predictive of poor behavioural compliance
during induction include younger age (<4 yrs), temperament
(shy, inhibited, dependent, withdrawn) and a brief time for
preoperative preparation.5,6 Children accompanied by calm
parents are less likely to be anxious during induction of
anaesthesia than those with anxious parents.7 Children with
previous negative experience of anaesthesia or hospital-
isation, and those with multiple previous hospital admissions
may also be at increased risk of anxiety, although in older
children, the effects of previous negative experiences may
decrease as they develop a more complete understanding of
the benefits of surgery and anaesthesia.
The age of the child also influences the need for premed-
ication in other ways. Before the emergence of separation
anxiety at around 6e8 months of age, infants respond to
soothing and comfort from a surrogate caregiver: sedative
220
 Anxiolytic premedication

the drug(s) and dose given, its effectiveness and if there were
Table 1 Alternative methods for managing preoperative any adverse events before or after surgery.
anxiety in children The practicalities of sedative premedication may vary be-
tween different groups of patients, institutions, cultures and
Anxiolytic strategies Practical examples countries. The timing of giving the drug is key to optimising its
Pre-hospital information Information leaflets, books,
efficacy whilst minimising potential delays to the operating
and preparation videos, hospital and operating
theatre tours, ‘social stories’ theatre schedule. It requires clear communication with the
and engagement with clinical preoperative nursing and operating theatre teams about when
psychologists the premedication should be given. Premedication should be
Play therapy Interaction with trained play withheld unless there is reasonable certainty that the surgery
therapists using visual aids will proceed; the child’s fasting status should be confirmed
and toys, and accompanying before dosing. Sedative drugs should only be given in a safe
patient to operating theatre environment where the patient can be observed appropriately
Distraction techniques Blowing bubbles, toys, videos and where resuscitation equipment is available. Ideally, a
and games sedated child should be monitored at all times on a tilting trolley
Engagement with Handling/personalising mask, in the ward, and should be transferred to the operating theatre
anaesthetic technique ‘blowing up the balloon’ and complex with portable suction and a self-inflating bag-valve
building anaesthetic circuit mask, accompanied by an appropriately trained member of
Environmental adjustment Lighting, music, minimal staff. In the event of respiratory depression or reduced
extraneous noise, fewest conscious level, treatment should be supportive, providing
healthcare staff possible and airway protection and ventilatory support as required. The use
hypnosis
of reversal agents, such as naloxone for opioids and flumazenil
Actively involving parents/ Parental presence for for benzodiazepines, should be carefully considered.
carers induction (also dependent on
parental anxiety levels)
Communication aids Communication ‘passports’ Choice of premedication
(information about the child’s
needs, routines and A number of agents are available for use as sedative pre-
communication strategies), medication. Drugs commonly used include benzodiazepines
use of Makaton and symbol (midazolam and temazepam), a2-adrenoceptor agonists
charts (dexmedetomidine and clonidine), N-methyl-D-aspartate
Relaxation techniques Breathing and relaxation (NMDA) receptor antagonists (ketamine) and opioids. The key
exercises, hypnosis and features of these are outlined in Table 2. Multiple factors in-
immersive reality
fluence the choice of drug, including the formulation, phar-
macological profile and contraindications of the drug; the
premedication is not required and is seldom used. In toddlers degree of cooperation from the child; and a history of agitation
and preschool-age children, separation anxiety remains a after anaesthesia. For example, where a child is anxious yet
problem, and their inability to understand the purpose of still willing to take an oral premedication, oral or buccal
anaesthesia or rationalise behaviour may easily make induc- midazolam is reliable. If the unpleasant taste causes a child to
tion of anaesthesia seem threatening. At the same time, their refuse it, oral clonidine may be more suitable. If a child refuses
strength and mobility continue to increase, making it partic- oral premedication, dexmedetomidine, which can be given by
ularly important to consider anxiolytic strategies. By around 5 the intranasal route, is a useful alternative.
yrs old, children have a more developed sense of self and of
potential harm. However, they are also better able to respond
to explanations and reason, and some may engage well with Midazolam
non-pharmacological anxiolytic strategies. Adolescents are Midazolam is used commonly because of its familiarity, quick
less likely to report anxiety spontaneously and are less likely onset and brief duration of action. It is an effective
to appear anxious behaviourally because of social expecta-
tions. Underlying baseline anxiety or depression, fearful
temperament and somatisation are possible predictors of Box 1
preoperative anxiety in these patients.8 The need for pre- Conditions in which sedative premedication may be
medication can be discussed with children as they get older, contraindicated
and can be offered as an option.

Anticipated difficult airway

Practical and safety considerations Obstructive or central sleep apnoea
Increased risk of aspiration
The need for premedication, and the identification of any
Severe renal or hepatic impairment
potential contraindications to it, should be part of every pae- Altered conscious level or increased intracranial pressure
diatric preanaesthetic assessment and a careful, individu- Acute systemic illness
alised risk/benefit assessment must be made for each patient New or unexplained reduction in oxygen saturations on air
(Box 1). When discussing the use of a premedication with the Upper respiratory tract infection
parents and child (where appropriate), the expected effects of Previous adverse or allergic reaction to proposed
medication
sedation should also be explained. If the child has received
sedative premedication previously, it is useful to determine

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Anxiolytic premedication
BJA Education - Volume 20, Number 7, 2020

Table 2 Summary of the key characteristics of sedative premedications

Drug, formulation, Mechanism of Age group Suggested dose Onset (min) Duration Advantages Limitations and adverse
and route action effects

1
Oral midazolam 2.5 GABAA receptor 1 monthe18 0.25e0.5 mg kg 30e45 45e60 min Reduced Paradoxical agitation and
mg ml 1 solution agonist yrs (maximum 20 PONV post-anaesthetic
mg) excitation; unpleasant
taste
Buccal midazolam 10 GABAA receptor 6 monthse18 0.3 mg kg 1 20 30e45 min Quick onset Paradoxical agitation and
mg ml 1 solution agonist yrs (maximum 10 of action; post-anaesthetic
mg) better excitation; dose limit 10
patient mg
compliance
Intranasal or buccal Selective a2- >1 yr old 2 mg kg 1 (range: 25 40e135 min Intranasal Caution in patients with
dexmedetomidine adrenoceptor 1e4 mg kg 1; (depending on dose) option; Grade 2/3 heart block
200 mg ml 1 agonist maximum 200 shorter half- (unless paced),
injection mg) life than uncontrolled
clonidine hypertension, and digoxin;
intranasal is by mucosal
atomisation device (note
dead space)
Oral clonidine 100 mg Central a2- 6 monthse18 4 mg kg 1 45e60 45e90 min Tasteless Caution in patients with
tablets or 10 mg ml 1 adrenoceptor yrs (maximum 200 liquid; long cardiovascular disease/
solution agonist mg) ‘window’ of instability
action
Temazepam 10 mg GABAA receptor 12e18 yrs 10e20 mg 60 12e140 min Useful if Long time to onset
1
tablets or 2 mg ml agonist (maximum 10 maximum
solution mg) dose of
midazolam
exceeded
Ketamine oral/i.m. Primarily NMDA 2e18 yrs Oral: 5e8 or 3 mg 10e15 3h Quick onset; Increased salivation,
(10 or 50 mg ml 1) receptor kg 1 in useful in hallucinations, emergence
antagonist combination combination delirium, and PONV at
with with higher doses;
midazolam; i.m.: midazolam anaesthetists must be
4e5 mg kg 1; i.v.: present at all times if i.m./
1e2 mg kg 1 i.v.
Morphine (2 mg ml 1
m-opioid 6 monthse18 0.2 mg kg 1 20e30 1e2 h Analgesic Rarely used as sole agent;
solution) receptors yrs (maximum 10 properties; risk of respiratory
mg) useful in depression and apnoea
combination

preoperative anxiolytic, may cause anterograde amnesia by
inducing a dissociation between explicit and implicit memory,
and reduces postoperative nausea and vomiting (PONV).
However, these amnestic effects may result in children dis-
playing more anxious behaviour in the immediate post-
operative period.9 The oral preparation has a bitter taste,
which might make some children refuse it or spit it out. Some
practitioners mask this by adding it to a small volume of a
flavoured drink. Buccal midazolam has a quick onset, may be
better tolerated by some children and does not require them
to swallow the medication. Although it is possible to give
midazolam by the intranasal route, the low pH of the prepa-
ration can cause not only pain, but also bleeding; this route is
best avoided.
Paradoxical reactions to midazolam occur in a small pro-
portion of children at variable times after dosing. This may
present with a brief period of sedation followed by aggression,
increased anxiety, agitation, violent crying, disorientation,
hallucinations and an inability to be calmed by parents. A
paradoxical reaction may be difficult to distinguish from an
agitated and anxious child who has received inadequate
premedication, but the key features are that distress occurs
after the administration of the premedication, after a brief
period of sedation, and does not improve with an additional or
increased dose of premedication. Children receiving higher
doses of midazolam appear to be at increased risk of para-
doxical reactions.10 Responder rates suggest that smaller
doses (0.25e0.5 mg kg 1 depending on the preparation used) of
midazolam are almost as effective as higher doses (0.75e1.5
mg kg 1) and little advantage is gained by increasing the
dose.11 Midazolam is also associated with an increased inci-
dence of postoperative agitation.
a2-adrenoceptor agonists
Dexmedetomidine is a highly selective a2-adrenoceptor
agonist that provides anxiolysis and sedation, whilst
providing additional benefits, including analgesic effects and
avoidance of respiratory depression. The sedation provided by
dexmedetomidine resembles a natural sleep, and meta-
analyses show it to be at least as effective in decreasing pre-
operative anxiety when compared with midazolam.12 How-
ever, dexmedetomidine does not provide any amnestic effects
and has a longer time to onset and longer duration of action
than oral midazolam. Bradycardia, or decrease in resting heart
rate, is a predictable response to dexmedetomidine, and it
should be used with caution in patients with severe ventric-
ular dysfunction and advanced atrioventricular block, and
those taking medications, such as digoxin or beta blockers. A
biphasic effect on arterial pressure may also be seen, and so it
should be avoided in patients with uncontrolled
hypertension.
Clonidine is another a2-adrenoceptor agonist that is more
widely available at most hospitals. It has many of the ad-
vantages and disadvantages of dexmedetomidine. It is given
orally, usually by giving the i.v. preparation, which is
tasteless. It has a slow onset of action and long duration of
action, and so provides a long ‘window’ of sedation before
surgery, but prolonged sedation after surgery. It should be
used with due caution, as it may induce hypotension and
bradycardia.
Anxiolytic premedication
Ketamine
Ketamine has sedative, anxiolytic and analgesic properties,
and a rapid onset of action. It may cause hallucinations,
random limb movements, increased salivation, hyperventi-
lation and significant emergence reactions, particularly
when given at the higher doses required when using as a
sole premedication. It is also emetogenic. Children receiving
ketamine should be nursed with close observation in a quiet
area. Giving midazolam in combination with ketamine al-
lows a lower dose to be given. Ketamine can be given i.m. in
cases where all other methods of managing perioperative
anxiety sufficiently to achieve safe anaesthesia have failed
and the procedure is felt to be necessary, or if alternative
drugs are not available. It is highly lipid soluble and is
rapidly absorbed after i.m. administration. This may be
painful and traumatic for the child, and may also require
physical restraint for the injection. The parents should be
counselled about this beforehand.
Flumazenil
Flumazenil competitively antagonises the effects of benzo-
diazepines. It may be given as a reversal agent in patients
who develop significant respiratory depression or apnoea
after iatrogenic benzodiazepine oversedation, provided
there are no contraindications (in particular, flumazenil
may precipitate seizures in patients taking prolonged
benzodiazepine therapy for epilepsy).13 It is given i.v. at an
initial dose of 10 mg kg 1 over 15 s (up to a maximum dose of
200 mg). The peak effect of a single dose occurs 6e10 min
after administration. The duration of action of flumazenil is
brief and re-sedation may occur, requiring further doses.
Infusions of flumazenil are unlicensed in children, but can
be given. It is also not licensed for use in children aged <1 yr.
It is worth noting that flumazenil does not consistently
reverse the central respiratory depression that occurs after
benzodiazepine overdose. The use of flumazenil to reverse
paradoxical agitation as a result of midazolam administra-
tion has also been described.14,15 Common adverse effects of
flumazenil include anxiety, nausea, vomiting, headache and
palpitations.
Special considerations
Obstructive sleep apnoea
Sedative premedication in children with obstructive sleep
apnoea (OSA) may cause pre- and postoperative airway
obstruction and desaturation. However, a safe and non-
traumatic induction of anaesthesia is not possible without
premedication for some children. Thus, the appropriate sed-
atives should be used with due caution and when indicated,
with support from anaesthetists. Midazolam may increase
supraglottic airway resistance, induce central apnoeas and
decrease the arousal response to hypoxia and hypercarbia.16
Therefore, it should be used with caution.17 Dexmedetomi-
dine causes a decrease in minute ventilation and increases
arterial carbon dioxide, but this occurs at a level similar to
‘profound sleep’, suggesting a theoretical advantage over
midazolam. Airway patency and tone are also maintained.18
Ketamine may also offer a theoretical advantage over mid-
azolam as upper airway patency is maintained, although the
associated hypersalivation may cause problems.
BJA Education - Volume 20, Number 7, 2020 223
Anxiolytic premedication

Obesity (i) Benzodiazepine (e.g. midazolam) and ketamine.

(ii) Benzodiazepine and a-2 agonist (clonidine or
Obesity is associated with a number of conditions that need to
dexmedetomidine).
be considered when prescribing sedative premedications,
(iii) Benzodiazepine or a-2 agonist and an opioid.
including OSA and gastro-oesophageal reflux. Achieving
optimal drug dosing in obese children is challenging. The The common practice in our institution is to use buccal or
physiological changes that occur can affect the pharmacoki- oral midazolam in combination with intranasal dexmedeto-
netics of many drugs, and failure to adjust drug dosing midine. It is important to apply caution when using combined
appropriately may result in inadvertent toxicity or therapeutic agents in patients at risk of airway obstruction or respiratory
failure. There remains a lack of pharmacokinetic studies in depression, as the combination of synergistic medications
obese children, and the available evidence is complicated by may increase the risk of overdosage. The combination of
variations in the BMI percentile thresholds used to define midazolam and opioids in particular is associated with an
obesity. Drug dosing guidance (where available) is typically increased risk of respiratory depression.21
derived from data in obese adults.
There are some key pharmacokinetic principles:
Melatonin as a premedication
(i) Absorption appears unaltered (based on limited data in
Melatonin has been used for both sedation and sleep regula-
obese adults).
tion. In adults, melatonin may be effective in reducing pre-
(ii) Drug distribution alters as both fat mass and lean body
operative anxiety.22 Its safety profile makes it an appealing
mass increase, but not proportionally.
alternative to other drugs, as it is associated with a lower
(iii) Dose adjustments are determined by the physicochem-
incidence of post-anaesthetic sleep disturbance than mid-
ical properties of the drug:
azolam or placebo, and produces less post-anaesthetic exci-
(a) Ideal body weight should be used for relatively hy-
tation than midazolam.23,24 Trials assessing the effects of
drophilic drugs (e.g. morphine).
melatonin in paediatric patients have produced conflicting
(b) Adjusted body weight may be used for those medi-
results. Some studies suggest that it may be as effective an
cations that partially distribute to adipose tissue (e.g.
anxiolytic as midazolam.24,25 However, others contradict
dexmedetomidine and clonidine).
this.23 This may relate to the differing dosing regimens used,
(c) Initial doses of lipophilic drugs may need to be
differences in outcome measures used, and the potential for
increased for an adequate response and should be
inter-rater reliability. Those studies that did demonstrate the
based on total body weight (e.g. benzodiazepines and
equivalence of melatonin to active controls used higher
ketamine).
dosing regimens than studies that did not. There is limited
(iv) Changes in protein binding are not significant clinically.
evidence to support the routine use of melatonin for
(v) The impact of obesity on drug metabolism may differ
premedication.
greatly, depending on the metabolic pathway and the
drug.

It can be challenging to apply these principles in practice.

For example, in obese adult patients, the volume of distribu-
tion of midazolam is increased, and it is suggested that a
loading or initial dose is based on total body weight, with
maintenance doses calculated on ideal body weight.19 As
clearance is unchanged, prolonged sedation may occur from
the larger dose required to achieve initial adequate plasma
concentrations. Information regarding its dosing in obese
paediatric patients is limited. Although dosing on ideal body
weight may result in a reduced clinical response, this
approach has been advocated to minimise the risk of signifi-
cant respiratory depression.20 The paucity of evidence and
guidance means that the experience and judgement of the
clinician in managing these patients are vital. The necessity to
achieve therapeutic effect must be balanced against the risks
posed by overdosage.
Previous experience of inadequate premedication
For some children, preoperative sedation may not have been
adequate or effective. Factors that may lead to inadequate
sedation include the timing of administration relative to in-
duction of anaesthesia, the agent used, the route, the dose and
the possibility of paradoxical agitation, especially with mid-
azolam. If the child previously spat out oral medication, giving
a drug by the intranasal route may ensure better drug delivery.
Where a low dose was previously used unsuccessfully, a
higher dose of the same agent or a combination of synergistic
agents can be effective. Useful combinations include:
Declaration of interests
The authors declare that they have no conflicts of interest.
MCQs
The associated MCQs (to support CME/CPD activity) are
accessible at www.bjaed.org/cme/home for subscribers to BJA
Education.
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